'Mix and Match' Proteins Found on Leukemia, Other Cells

[Guest guest]

News

Published online: 8 September 2006

'Mix and match' proteins found

Rearranged peptides may play big role in immunity.

Kerri

Surprise: proteins aren't as fixed as thought.

Proteins seem to be more changeable than biologists once thought.

Human cells can apparently shuffle the components of these molecules —

dicing them up and reordering them to make new structures.

This ability might allow the body to boost our immune response

against infected cells. And researchers are optimistic that it could

enhance their understanding of how the immune system recognizes cells

that need to be attacked.

DNA codes for proteins by first producing an RNA template, which can

be chopped up and reassembled depending on which specific version of

a protein is needed. Biologists had long assumed that once this

mixing was done at the RNA level, the proteins made were set in

stone.

But in 2004, researchers found that this wasn't always true — at

least not for proteins found in skin-cancer cells. Some of these

molecules seemed to have been cut up, had sections removed, and then

been glued back together1. Such 'protein surgery' has also been seen

in plants and single-celled organisms.

Now Edus Warren of the Fred Hutchinson Cancer Research Center in

Seattle, Washington, and his colleagues show that even more chopping

and changing occurs in proteins found in some normal cells. In this

week's Science2, they show that proteins can be cut up, rearranged

and glued back together, vastly increasing the number of different

structures that can be made from an original protein. And as this was

seen in proteins that are found in normal cells, it suggests that

such rearrangements might be far more common than had been

appreciated.

For the chop

The team studied a group of short proteins called peptides, which are

found on the surface of cells. These molecules are used by components

of the immune system called T cells to determine whether a cell is

normal or a foreign invader.

The peptides are generally formed when the proteins made inside the

cell are degraded: a piece of cell machinery called the proteasome

chews up proteins and spits out these chunks. But the proteasome has

other tricks too. " The proteasome can splice peptides together, " says

Warren. " Every once in a while, new peptide bonds will be created,

not just destroyed. "

It isn't clear why this happens, or what the newly spliced peptides

do. But as the molecules end up on the cell's surface, they are

probably involved in the cell's " immunologic identity " , says Warren.

In the latest study, peptides made in this 'mix and match' fashion

were found on cells from a leukaemia patient who had received a bone-

marrow transplant. The patient's rearranged peptides unfortunately

triggered an immune reaction from the T cells in the transplanted

marrow. The rearranged proteins are of a type commonly found in many

cells, including non tumorous ones.

The researchers speculate that peptide splicing might also help the

immune system to recognize cells that have been invaded by a virus.

As they replicate inside a cell, viruses create new peptides on the

cell's surface. If that cell could then rearrange these peptides, it

might increase the immune system's chance of recognizing the foreign

invader, they say. This idea has not been tested.

It is not yet known whether all cells use their proteasomes to

shuffle all types of proteins, or whether the mechanism is specific

to peptides used by the immune system. Warren suspects that the

mechanism will be found elsewhere. " There is no reason why cells

could not have learned how to use this mechanism to their advantage.

But I don't think that people have ever looked, " he says.